Malonato platinum anti-tumor compounds

ABSTRACT

Malonato platinum coordination compounds and a method of treating malignant tumors comprising the parenteral administration to an affected animal of a solution of the compound.

The invention described herein was made in the course of work under agrant or award from the Department of Health, Education and Welfare.

This is a continuation, of application Ser. No. 260,989, filed June 8,1972, now abandoned.

BACKGROUND OF THE INVENTION

The present invention relates to novel malonato platinum coordinationcompounds and to their use in cancer chemotherapy.

SUMMARY OF THE INVENTION

The invention provides platinum coordination compounds having theformula:

    [Pt(II)A.sub.x (OOC).sub.2 --CRR.sub.1 ] or

    cis or trans[Pt(IV)A.sub.x (OOC).sub.2 --CRR.sub.2)yLz]

wherein:

X = 1 or 2;

Y = 1 or 2:

Z = 0, 1 or 2,

Provided that when y = 2, z = 0 and when y = 1, z is greater than 0;

R and R₁ are selected from the group consisting of H, lower alkyl, aryl,aralkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, OH, or are combinedwith the carbon atom to form a cycloalkyl or cycloalkenyl group, andsubstituted derivatives thereof;

WHEN X = 1, A is HR₂ N--CHR₃ --CHR₄ --NR₅ H and when x = 2, A is H₂ NR₆a heterocyclic amine or an amino acid, wherein R₂, R₃, R₄ and R₅ are thesame or different and are selected from the group consisting of H, CH₃,C₂ H₅, hydroxy and lower alkoxy provided that R₂ and R₅ may also be arylor aralkyl, and each R₆ is the same or different and is selected fromthe group consisting of H, lower alkyl, aryl, aralkyl, hydroxy loweralkyl, hydroxyl and alkoxyl amines, alkoxylalkylamines wherein all ofsaid alkyl groups are lower alkyls and heterocyclic substituentsincluding said N as a ring member;

When z = 1, L is a bidentate anionic ligand, and

When z = 2, L is a monodentate anionic ligand.

The invention also relates to a composition and method for treatingmalignant tumors in animals comprising parenterally administering to ananimal affected with a malignant tumor a solution containing a platinumcoordination compound as defined hereinabove in an amount sufficient tocause regression of the tumor.

DETAILED DESCRIPTION OF THE INVENTION

Platinum coordination compounds and methods for their production aredescribed by J. C. Bailar, Jr., The Chemistry of the CoordinationCompounds, Reinhold Publishing Corp., N.Y., 1956, Chap. 2; J. Lewis etal, Modern Coordination Chemistry: Principles and Methods, IntersciencePublishers, Inc., N.Y., 1960 and Kauffman Inorganic Synthesis, 7,McGraw-Hill Book Co., Inc., N.Y., 1963.

Platinum (II) forms dsp² coordination compounds which have a squareplanar arrangement in space. Platinum (IV) forms d² sp³ coordinationcompounds which have an octahedral arrangement in space.

The coordination compounds of the invention include the cis and transisomers of platinum (II) and platinum (IV) which contain the bidentatemalonato ligand which may be substituted or unsubstituted. The malonatoligand may contain substituents selected from the group consisting oflower alkyl, (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, etc.);aryl, (e.g., phenyl; lower alkyl-, lower alkenyl-, halo-, nitro-, loweralkoxy-substituted phenyl and naphthyl); aralkyl, (e.g., phenylmethyl(benzyl), 2-(1-naphthyl)methyl); alkenyl, (e.g., 4-amino-1-butene,allyl); cycloalkyl, (e.g., cyclopropyl, cyclohexyl, etc.); cycloalkenyl,(e.g., 2-cyclopenten-1-yl, 2-cyclohexen-1-yl); alkoxy, (e.g., methoxy,ethoxy, etc.), and hydroxy. Also suitable are the1,1-cycloalkylenedicarboxylic acids, (e.g., 1,1-cyclopropanedicarobxylicacid, 1,1-cyclobutanedicarboxylic acid, etc.) and the1,1-cycloalkenyldicarboxylic acids, (e.g., 1,1-cyclopropenedicarboxylicacid, 1,1-cyclobutenedicarboxylic acid, etc.)

The coordination compounds of the invention also contain two monodentateammonia or primary or heterocyclic amine ligands, i.e., when x in theabove formula is 2 or one bidentate amine ligand, i.e., when x is 1.

Suitable monodentate amine ligands include lower alkyl amines, (e.g.,methyl-, ethyl-, n-propyl-, isopropyl-, n-butyl- amines, etc.), arylamines, (e.g., aniline), aralkyl amines, (e.g., benzylamine), hydroxylower alkyl amines, (e.g., ethanolamine, propanolamine, etc),hydroxylamine, lower alkoxy amines (e.g., methoxylamine, etc.),alkoxyalkylamines (e.g., methoxymethylamine, etc.), and heterocyclicamines (e.g., pyridine and aziridine). Also included are the aminoacids, i.e., R₇ --CHNH₂ --COOH wherein R₇ is H, lower alkyl (e.g.,methyl, isopropyl, etc.), hydroxy lower alkyl (e.g., hydroxymethyl,hydroxyethyl, etc.), aralkyl (e.g., benzyl, etc).

It is to be understood that the coordination compounds of the inventionmay include two identical or different monodentate ligands.

Suitable bidentate amine ligands include the substituted andunsubstituted primary and secondary ethylenediamines. One or both of thecarbon atoms of the ethylenediamine may contain substituents such aslower alkyl (e.g., methyl, ethyl), hydroxyl, alkoxy (e.g., methoxy,ethoxy, etc). Secondary ethylenediamines wherein one or more of theamine groups contains substituents such as listed above for the carbonatoms of the primary amine and aryl (e.g., phenyl) and aralkyl (, e.g.benzyl) may also be utilized.

The Pt (II) coordination compounds specified herein do not exist asgeometrical isomers; however, the Pt (IV) compounds exist as cis andtrans isomers. It is to be further understood that the invention isinclusive of the cis and trans isomers.

The Pt (IV) coordination compounds may also contain two monodentate orone bidentate anionic ligand where only one malonato ligand is present,i.e., where y = 1 in the above formula.

Suitable monodentate anionic ligands include chloride, bromide, iodide,nitrite, hydroxide, nitrate, sulfamate, etc. Among the bidentate anionicligands which may be present are oxalate, pyrophosphate, dithioxalate.

It is to be understood that the invention includes those coordinationcompounds containing mixed monodentate anionic ligands.

The preferred compounds are those wherein R and R₁ in the above formulaare H, methyl or ethyl, i.e., malonatoplatinum, methylmalonatoplatinumand ethylmalonatoplatinum coordination compounds. The most preferred Pt(II) compounds are those malonatoplatinum (II) compounds of the aboveformula wherein x = 1 and R₂, R₃, R₄ and R₅ are each H, i.e.,malonatoethylenediamine platinum (II),methylmalonatoethylenediamineplatinum (II) andethylmalonatoethylenediamineplatinum (II); and wherein x = 2 and each R₆is H, i.e., malonatodiammineplatinum (II),methylmalonatodiammineplatinum (II) and ethylmalonatodiammineplatinum(II).

The preferred Pt (IV) compounds are those wherein x = 2, each R₆ is Hand y = 2, i.e., bismalonato (or bismethylmalonato or bisethylmalonato)diammine platinum (IV).

The coordination compounds of the invention may be prepared by one of avariety of well-known methods. A general method of preparation of the Pt(II) coordination compounds is as follows: Starting compounds having theformula cis-[Pt A(Hal)₂ ] wherein Hal is I, Cl or Br and A is onebidentate or two monodentate amine ligands (prepared by the method of S.C. Dhara, Indian J. Chem., Vol 8, p. 193 (1970)) are reacted with silvernitrate to form the diaquo complex. The latter is then reacted with themalonate ion to form the coordination compounds of the invention. Thismethod is represented by the following reaction scheme:

    cis-[Pt ACl.sub.2 ] + 2AgNO.sub.3 + 2H.sub.2 O) → cis-[Pt A(H.sub.2 O) .sub.2 ](NO.sub.3).sub.2 + 2AgCl

    cis-[Pt A(H.sub.2 O).sub.2 ](NO.sub.3).sub.2 + H.sub.2 C-(COO).sub.2 → [Pt A(OOC).sub.2 -CH.sub.2 ] + 2NO.sub.3 .sup.- + 2H.sub.2 O

wherein A is one bidentate amine ligand or two monodentate amineligands.

The following non-limiting examples are illustrative of the methods forpreparing the compounds of the invention.

EXAMPLE 1 Malonatodiammineplatinum(II) [Pt(NH₃)₂ (C₃ H₂ O₄)]

Reactions:

    [Pt(NH.sub.3).sub.2 Cl.sub.2 ] + 2AgNO.sub.3 + 2H.sub.2 O) → [Pt(NH.sub.3).sub.2 (H.sub.2 O).sub.2 ](NO.sub.3) + 2AgCl I

    [pt(NH.sub.3).sub.2 (H.sub.2 O).sub.2 ](NO.sub.3).sub.2 + C.sub.3 H.sub.2 O.sub.4 2- → [Pt(NH.sub.3).sub.2 (C.sub.3 H.sub.2 O.sub.4)] + 2NO.sub.3 .sup.- +2H.sub.2 O.                             II

silver nitrate (22.55g -- slightly less than the stoichiometric amountin order to avoid silver contamination) was dissolved in water (50 ml.)and added to [Pt(NH₃)₂ Cl₂ ] (20g) in a 250 ml. conical flask. Thecontents were warmed (60° C.) on a hot plate with rapid stirring untilthe silver chloride precipitation was complete and the mother liquor wasalmost colorless. The silver chloride was filtered off using a fine poresintered glass filter and the precipitate was washed several times withhot water to give a total filtrate volume of 100-200 ml.

Malonic acid (13g -- a twofold excess) was dissolved in water (30 ml.)and neutralized with a solution of KOH (˜13g in 30 ml.) to pH 5-6. Theresulting potassium malonate solution was added to the platinumcontaining filtrate and the mixture was carefully warmed (to avoid"bumping") on the hot plate until white crystals of the product startedto form in great quantity. The mixture was then cooled to roomtemperature and the product filtered off. The filtrate was reheated for5-10 minutes and cooled to 0° C. to collect a further crop. The crudeyield at this stage was 20.5g (93%).

The product was recrystallized by dissolving in boiling or near boilingwater. The above yield (20.5g) required about 3 liters of boiling waterfor complete dissolution. Malonic acid 1g/L was dissolved in the waterto suppress any hydrolysis.* The filtered solution was cooled to 0° C.to give white fluffy needles (18.25g-83%).

The crystals decompose between 185°-190° C. The structure of the productwas verified cia an i.r. spectrum. Solubility of the product is low incold water, i.e., 20 mg/100 mls at 20° C. and 43 mg/100 mls at 37° C.,but higher in near boiling water (90°-100° C.)˜65g/100 ml.

The empirical composition was verified by elemental analysis:

Malonatodiammineplatinum(II) [Pt(NH₃)₂ (C₃ H₂ O₄)]

Calculated for C₃ H₈ N₂ O₄ Pt.C.: 10.88; H: 2.43; N: 8.46: Pt 58.9;Found C: 10.67; H: 2.35; N: 8.54; Pt 58.7.

EXAMPLE 2 [Pt (en) (C₄ H₄ O₄)] (en = H2N(CH₂)₂ NH₂ ; C₄ H₄ O₄ ²⁻ = O₂ CCH(CH₃) CO₂ ²⁻)

Silver nitrate (3.64g) was dissolved in 20 ml of water and added to[Pt(NH₂)₂ (CH₂)₂ CL₂ ] (3.5g) suspended in water (30 ml.) in a conicalflask. The mixture was stirred on a warm hot plate for 5-10 minutesuntil all the yellow platinum complex had dissolved to give a yellowliquor plus a copious white silver chloride precipitate. The mixture wasfiltered through a fine pore filter and the precipitate washed twicewith small volumes of hot water. The clear filtrate plus washings wasadded to an aqueous solution of methylmalonic acid (2g in 20mls) whichhad been adjusted to pH 5-6. The mixture was heated to about 80° C. forfive minutes and then cooled to 0° C. The shiny white crystals whichformed were filtered and washed with cold water and acetone (Yield2.65g). The mother liquor plus aqueous washings was reduced to abouthalf its original volume (˜30 mls) to yield a second crop on cooling to0° C. (Yield 0.85g). Total Crude yield was 3.50 gms (88%). The complexwas recrystallized from a minimum volume of boiling water (around 250mls) with filtration through a fine pore filter prior to cooling to 0°C.

Yield of shiny white leaflets 2.96g (74%).

Calculated for C₆ H₁₂ N₂ O₄ Pt: C:19.41 H 3.26 N:7.55; Found C:19.11 H3.61 N:7.89.

A second crop (0.33g-8%) was obtained by reducing the bulk of the motherliquor.

EXAMPLE 3 trans-[Pt IV(NH₃)₂ (mal)₂ ]

Silver nitrate (5.45g) was dissolved in water (30 ml) and added to trans[Pt(NH₃)₂ Cl₄ ] (3g) suspended in water (30 mls) containing concentratednitric acid (3 ml). The contents were warmed on a hot plate (70°-80° C.)and stirred for at least one hour. The mixture was filtered through afine pore sintered glass filter to remove the silver chloride. Theprecipitate was washed twice with a small volume of hot water. The clearfiltrate plus washings was tested with a drop of 1M KCl solutions todetermine if excess silver chloride was present. (If the test ispositive, sufficient KCl is added dropwise to the bulk solution until nosilver chloride is precipitated.) The solution was refiltered and thefiltrate reduced to 20-30 mls in volume and cooled to 0° C. to yieldplate yellow crystals (presumably trans (Pt(NH₃)₂ (NO₃)₄ ]). These werewashed with a little cold water and then acetone (Yield 1.8g). A portionof this yield (1g) was dissolved in a minimum of hot water to whichsodium nitrate (0.2g) had been added. This solution was filtered into anaqueous solution of malonic acid (0.5g -- a slight excess) which hadbeen adjusted to pH 5-6 with sodium hydroxide. White nucro-crystals ofthe complex quickly form on cooling. These were filtered off and washedwith cold water and acetone. (Yield 0.7g -- 30-40%).

Calculated for C₆ H₁₀ N₂ O₈ Pt C:16.63 H 2.33 N:6.47; Found C:16.60 H2.64 N:6.80.

GENERAL STRUCTURE CONFORMATION

The malonate group is shown to be coordinated to the platinum by theobserved change in the electronic spectra on going from the aquo to themalonate species. Thus, structures such as [Pt(NH₃)₂ (H₂ O)₂ ]₂ (H₂ C₃O₄)] are ruled out confirming the analytical data. Similarly, zero-timeconductivity measurements support a neutral compound. The i.r. spectrashow the presence of coordinated carboxyl groups (1600-1650 cm⁻¹ and1400 cm⁻¹) with no CO₂ H groups (which would show at 1700-1750 cm).Finally the carboxyl group vibrations are compatible with a chelatedstructure as compared to oxalate complexes of known structures.

The compounds of the invention were tested for anti-tumor activity usingour standard screening tumor, solid sarcoma 180 tumer in female Swisswhite mice, following standard protocols for this testing as set by theNational Cancer Institute. (Cancer Chemotherapy Rep., 25(1962)).

For these tests an S 180 tumor taken from a sacrificed mouse wasdisected free of superfluous tissue and cut under sterile conditionsinto approximately 10 milligram size pieces. These tissue pieces werethen implanted by trocar in the left axillary region, subcutaneously, innew mice. The mice were, on the average, approximately four weeks oldand weighed 18-20 grams. Taking day 0 as the day of implant, the animalswere sacrificed on day 10. The tumors were excised and weighed and theratio of the weights of the tumors in mice in the treated animals to thecontrol set of animals was obtained. This ratio, multiplied by 100, isgiven as the T/C ratio in Table I.

For the first set of tests the coordination compound was freshlydissolved in sterile distilled water and injected intraperitoneally onday 1 into each of the test mice. The volume of the injection wasusually 1/2 ml. In some cases, in order to get an active dose into theanimal where the chemical was not soluble in this amount of solvent, afine dispersion was prepared of the dose needed for the test. Thus, someof our test results were obtained on animals where a slurry of thecompound was injected. These are so noted in Table I below. In addition,for some of the compounds, there was injected about 1 ml of solution,either in one single injection, or in 2 injections given a few hoursapart of 1/2 ml each. These injections were initially given in 4different dose levels for each new compound with 6 mice in each doselevel. The tests covered a dose range from a low ineffective dose, to anupper dose level which produced some deaths within the time period ofthe experiment. The results are set forth in Table I.

                                      TABLE I                                     __________________________________________________________________________    Tests of Antitumor Activity of Malonato and Substituted Malonato              Coordination                                                                  Complexes of Plantinum.                                                       Tumor-Sarcoma 180  Animal-Female Swiss white mice                             Single injections on days noted, intraperitoneally                            __________________________________________________________________________                     Day of           No. of                                      Coordination Complex                                                                           Injection                                                                           Dose Level                                                                            T/C                                                                              Deaths                                      __________________________________________________________________________    Malonatodiammineplatinum                                                                       1     10 mg/kg                                                                              76 0                                           (II) (slurry in H.sub.2 O)                                                                           15 mg/kg                                                                              38 0                                                                  20 mg/kg                                                                              64 0                                                                  25 mg/kg                                                                              31 0                                                                  30 mg/kg                                                                               7 1/6                                                                40 mg/kg                                                                              -- 6/6                                                                50 mg/kg                                                                              1  5/6                                                                60 mg/kg                                                                              -- 6/6                                         (solution in H.sub.2 O)                                                                        Daily for                                                                           4  mg/kg                                                                              54 0                                                            days 1-10                                                                           5  mg/kg                                                                              56 0                                                                  6  mg/kg                                                                              23 0                                                                  7  mg/kg                                                                              12 0                                           Methylmalonatodiammine-                                                       platinum(II) (Solution in H.sub.2 O)                                                           1     30 mg/kg                                                                              39 0                                                                  40 mg/kg                                                                              26 0                                                                  50 mg/kg                                                                              35 0                                                                  60 mg/kg                                                                               6 0                                                                  70 mg/kg                                                                              124                                                                              3/6                                                                80 mg/kg                                                                              -- 6/6                                         malonatoethylenediamine-                                                                       1     60      80 0                                           platinum (II)          80      138                                                                              0                                                                  100     85 0                                                                  120     50 0                                           ethylmalonatoethylenediamine-                                                                  1     40      72 0                                           platinum (II)          60      81 0                                                                  80      79 0                                                                  90      47 0                                                                  100     55 1                                                                  110     41 0                                                                  120     58 0                                           malonato-1,2 propylenediamine-                                                                 1     45      50 0                                           platinum (II)          60       9 1                                                                  75      16 3                                                                  90      -- 5                                           malonato-1,3 propylenediamine-                                                                 1     20      69 0                                           platinum (II)          40      79 0                                                                  60      21 0                                                                  80      35 1                                           methylmalonatoethylene-                                                                        1     30 mg/kg                                                                              78 0                                            diamineplatinum (II)                                                          (solution in H.sub.2 O)                                                                             40 mg/kg                                                                              80 0                                                                  50 mg/kg                                                                              51 0                                                                  60 mg/kg                                                                              26 0                                                                  70 mg/kg                                                                              20 1                                                                  90 mg/kg                                                                               4 1                                           ethylmalontodiammine-                                                                          1     30 mg/kg                                                                              57 0                                            platinum(II)                                                                  (solution in H.sub.2 O)                                                                             40 mg/kg                                                                              43 0                                                                  50 mg/kg                                                                              47 0                                                                  60 mg/kg                                                                              39 0                                                                  70 mg/kg                                                                              17 0                                                                  80 mg/kg                                                                              16 0                                           malonatoethylenediamine-                                                                       1     10 mg/kg                                                                              88 0                                            platinum (II)                                                                 (solution in H.sub.2 O)                                                                             20 mg/kg                                                                              58 0                                                                  40 mg/kg                                                                              18 0                                                                  45 mg/kg                                                                              49 0                                                                  50 mg/kg                                                                              35 0                                                                  55 mg/kg                                                                              38 0                                                                  60 mg/kg                                                                              15 3/6                                                                80 mg/kg                                                                              24 3/6                                         1,1-cyclobutanedicarboxylate                                                                   1     20 mg/kg                                                                              71 0                                           diammineplatinum (II)                                                                                40 mg/kg                                                                              60 0                                                                  60 mg/kg                                                                              38 0                                                                  80 mg/kg                                                                              42 0                                                                  100                                                                              mg/kg                                                                              69 0                                                                  120                                                                              mg/kg                                                                              18 0                                                                  160                                                                              mg/kg                                                                              62 4                                           malonatobis(methylamine)                                                                       1     80 mg/kg                                                                              58 0                                           platinum (II)          100                                                                              mg/kg                                                                              53 0                                                                  120                                                                              mg/kg                                                                              28 0                                                                  140                                                                              mg/kg                                                                              25 0                                                                  160                                                                              mg/kg                                                                              17 1                                                                  180                                                                              mg/kg                                                                              19 1                                           __________________________________________________________________________

In addition to the day 1 injections described above, in a number ofcases injections were delayed until day 8 of tumor growth. In thesecases the tumor was usually at least larger than 1/2 gm, as estimated bypalpation. The animals were then injected and observed for a period ofapproximately 60 days. Activity was measured by the number of animalswhose tumors had regressed to the vanishing point, while still allowingthe animal to survive for this time period. Such test results aredescribed in TABLE II below.

                  TABLE II                                                        ______________________________________                                        Tests of Large Sarcoma 180 Regressions by Malonato Co-                        ordination Complexes of Platinum.                                             Tumor-Sarcoma 180                                                                             Animal-Female Swiss white mice                                Single injections on Day 8 intraperitoneally in H.sub.2 O                     ______________________________________                                        solutions                                                                                              Total Number                                         Coordination Complex                                                                         Dose      of Regressions                                                                            Deaths                                   ______________________________________                                        malonatodiammine-                                                                            14 mg/kg  2           4                                        platinum(II)                                                                                 16 mg/kg  3           3                                                       18 mg/kg  4           2                                                       20 mg/kg  5           1                                        malonatoethylene-                                                                            40 mg/kg  3           3                                        diamineplatinum(II)                                                                          45 mg/kg  1           5                                                       50 mg/kg  2           4                                                       60 mg/kg  3           3                                        ______________________________________                                    

The results described in Tables I and II indicate that the compounds ofthe invention are very potent antitumor agents against the S 180 tumorin Swiss white mice.

Confirmatory tests of antitumor activity against the Walker 256Circinosarcoma in rats, and the ADJ/PC6A tumor in mice were conducted.The initial test results are shown in Table III and confirm the potentaction of the compounds of the invention against these other tumorsystems.

                  TABLE III                                                       ______________________________________                                        Confirmatory Tests of Antitumor Activity                                      Malonatodiammineplatinum(II)                                                  Tumor: Walker 256 Carcinosarcoma - Animal - Rat                               Single injection Day 1 in Oil, Intraperitoneally                              Dose           % Inhibition   Deaths                                          ______________________________________                                        10 mg/kg       100            0                                               20 mg/kg       100            0                                               40 mg/kg       100            0                                               80 mg/kg       --             0                                               Malonatoethylenediamineplatinum(II)                                           Tumor: Walker 256 Carcinosarcoma - Animal - Rat                               Single injection Day 1 in Oil, Intraperitoneally                              Dose           % Inhibition   Deaths                                          ______________________________________                                        10              1             0                                               20             25             0                                               40             100            0                                               80             100            0                                               160            --             all                                             Tumor: ADJ/PC6A - Animal - Mouse                                              Single injection Day 25 in Oil, Intraperitoneally                             Dose           % Inhibition   Deaths                                          ______________________________________                                         4             1.3            0                                               20              94            0                                               100            100            0                                               500            --             all                                             ______________________________________                                    

Samples of the malonato diammine and malonato ethylene diamino complexesof platinum(II) were submitted to the Drug Research and DevelopmentBranch of the National Cancer Institute for screening for antitumoractivity against the L1210 tumor in mice. The results obtained on thistumor system are shown in Table IV. They confirm the activity of thecompounds of the invention.

                  TABLE IV                                                        ______________________________________                                         Confirmatory Tests of Antitumor Activity at the                              National Cancer Institute.                                                    Tumor: L1210         Animal - Mice                                            Daily injectons Days 1-9, Intraperitoneally                                                                  % Increase                                     Coordination Complex Dose      in Lifespan                                    ______________________________________                                        Malonatodiammineplatinum(II)                                                                       50 mg/kg  163                                                                 25 mg/kg  133                                                                 12.5 mg/kg                                                                              115                                            Malonatoethylenediamineplatinum(II)                                                                50 mg/kg  101                                                                 25 mg/kg  160                                                                 12.5 mg/kg                                                                              151                                            (repeat test)        37.5 mg/kg                                                                              121                                                                 25 mg/kg  196                                                                 16.5 mg/kg                                                                              160                                                                 11 mg/kg  145                                            ______________________________________                                    

The malonatoplatinum coordination compounds of the invention arepreferably dissolved or suspended in water or other pharmaceuticallyacceptable carrier liquids. The parenterally administerable compositionshould preferably contain from about 0.5mg to about 10mg per ml., itbeing understood that the amount may vary greatly depending upon theparticular compound employed and the animal to be treated.

The platinum coordination compounds of the invention are preferablyadministered parenterally to an animal affected with a malignant tumor.The duration of treatment and the dose level, of course, will depend ineach case upon the size of the host animal, nature and size of thetumor, etc. Generally, however, a dose level of from about 20 to about200 mg/kg of body weight per day will be sufficient. It is to beunderstood, however, that the platinum coordination compounds compoundedwith a suitable pharmaceutical carrier in the same proportions asrecited above may also be administered orally at the same dosage levels.

We claim:
 1. Platinum coordination compounds having the formula:

    [Pt(II)A.sub.x ((OOC).sub.2 --CRR.sub.1)]

wherein: x = 1 or 2; R and R₁ are selected from the group consisting ofH, lower alkyl, aryl, aralkyl, alkenyl, cycloalkyl, cycloalkenyl,alkoxy, OH, or combine with the carbon atom to form a cycloalkyl orcycloalkenyl group; when x = 1, A is HR₂ N--CHR₃ --CHR₄ --NR₅ H and whenx = 2, A is H₂ NR₆ or an amino acid, wherein R₂, R₃, R₄ and R₅ are thesame or different and are selected from the group consisting of H, CH₃,C₂ H₅, hydroxy and lower alkoxy, provided that R₂ and R₅ may also bearyl or aralkyl and each R₆ is the same or different and is selectedfrom the group consisting of H, lower alkyl, aryl, aralkyl, hydroxylower alkyl, hydroxyl- and alkoxylamines, and alkoxyl alkyl amines. 2.The compound of claim 1 having the formula:

    [Pt(II)A.sub.x ((OOC).sub.2 --CH.sub.2)]

wherein: x = 1, and R₂, r₃, r₄ and R₅ are each H.
 3. The compound ofclaim 1 having the formula:

    [Pt(II)A.sub.x ((OOC).sub.2 --CH.sub.2)]

wherein: x = 2, and each R₆ is H.
 4. Malonato diammine platinum (II).